The main objective of the proposed studies is to analyze the in vivo pathogenesis and molecular mechanisms by which naturally-occurring edible plant flavonols produce small and large bowel adenocarcinomas. Quercetin and kaempferol are the most common flavonols, occuring as glycones, with ubiquitous distribution in widely varying concentrations in vegetables and fruits consumed by humans. It is estimated that humans in the USA consume about one gm per day of quercetin. We have demonstrated the mutogenicity of quercetin and koempferol for Salmonella typhimurium, and the intestinal carcinogenity (80%) of quercetin for rats. We hypothersize that quercetin and kaempferol glycones (non-mutagenic) are hydrolyzed by intestinal bacteria or intestinal bacteria or intestinal mucose to aglycones that in turn are converted into proximate or ultimate molecular carcinogenic species, most probably at the site of their formation. Molecular activation of quercetin or kaempferol is proposed to occur either through oxidation to quinonoid compounds followed by dehydrogenation to unstable, electrophilic flavonol-quinones; or by oxidation to Alpha, Beta-chalcone epoxides in a manner analogous to the carcinogen, safrole. Chemicals of interest will be synthesized by known methods and purified before use. Mutagenicity will be studied directly in Salmonella typhimurium TA 98 and l00, and following incubation with "S-9" or "S-13" mixes prepared from liver and intestinal epithelium, or norharmon. Induction of intestinal epithelial ornithine and S-adenosyl-L-methionine decarboxylases will be employed to directly assess mucosal short-term effects. Biotransformation products will be isolated by solvent extractions, and thin-layer, high pressure liquid, and gas-liquid chromatographic procedures. Structural analyses of proximate molecular species will be by ultraviolet, proton magnetic resonance, mass, and infrared spectrophotometric methods. Carcinogenicity of isolated, active compounds will be determined by oral or direct intrarectal administration to rats. Quercetin and, perhaps kaempferol, represent carcinogens of a new structural class, first identified in studies conducted by us. Their major effect on intestinal epithelium of rats suggests that they may represent carcinogenic hazard for humans who consume them in their diets. These studies will seek a molecular basis for their intestinal carcinogenic effects so that rational means of molecular prevention may be developed.